Targeted delivery of therapeutics such as siRNA may improve tumor treatment by increasing efficacy and minimizing side effects [see for example, Jain, R. K. Delivery of molecular and cellular medicine to solid tumors. J Control Release 53, 49-67, (1998); Jain, R. K. Delivery of molecular and cellular medicine to solid tumors. Adv Drug Deliv Rev 46, 149-168, (2001); Ruoslahti, E. Drug targeting to specific vascular sites. Drug Discov Today 7, 1138-1143, (2002); Ruoslahti, E. Specialization of tumour vasculature. Nat Rev Cancer 2, 83-90, (2002); and, Jain, R. K. Delivery of molecular and cellular medicine to solid tumors. J Control Release 53, 49-67, (1998); Satchi-Fainaro, R. et al. Targeting angiogenesis with a conjugate of HPMA copolymer and TNP-470. Nat Med 10, 255-261, (2004)].
Approaches to target siRNA in vivo have been challenging due to their rapid clearance, susceptibility to serum nucleases, endosomal entrapment, and stimulation of innate immunity [Whitehead, K. A., Langer, R. & Anderson, D. G. Knocking down barriers: advances in siRNA delivery. Nat Rev Drug Discov 8, 129-138, (2009)].
High-throughput technologies such as in vivo phage display have selected targeting peptides for a diversity of molecular targets [Akerman, M. E., Chan, W. C., Laakkonen, P., Bhatia, S. N. & Ruoslahti, E. Nanocrystal targeting in vivo. Proc Natl Acad Sci USA 99, 12617-12621, (2002); and Pasqualini, R. & Ruoslahti, E. Organ targeting in vivo using phage display peptide libraries. Nature 380, 364-366, (1996)], while whole-genome sequencing has provided an integrated dataset of genetic alterations in human cancer [Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061-1068, (2008)]. However, a unifying technology that is equally high-throughput and efficient is required to validate these hits in vivo and translate them into clinically meaningful therapies.